Pharmacological inhibition of FGFR by infigratinib reduces lipids associated with neurodegeneration in MOG35-55-induced EAE
Martin Berghoff1, Natascha Wallendszus1, Vinothkumar Rajendran1, Gerhard Liebisch2, Srikanth Karnati3, Ranjithkumar Rajendran1
1Department of Neurology, University Hospital Giessen, 2Institute of Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, 3Institute of Anatomy and Cell Biology, University of Würzburg
Objective:
To characterize the effects of pharmacological FGFR inhibition on lipids associated with neurodegeneration in EAE.
Background:
Analysis of human brain tissue has shown that FGF and FGFR modulate the pathogenesis of multiple sclerosis (MS). Expression of lipids associated with neuronal degeneration is changed in the CSF of patients. The lipids, ceramide and LPC are associated with axonal damage, demyelination, and vascular leakage. Clinical trials have found that FGF-based drugs have beneficial effects on the lipid metabolism. We hypothesized that pharmacological FGFR inhibition reduces the expression of lipids in EAE.
Design/Methods:
The selective FGFR inhibitor infigratinib (30 mg/kg) was administered orally over 10 days either from the time of EAE induction (prevention experiment) or onset of symptoms (suppression experiment) in MOG35-55-induced EAE. At the peak of disease (days 18-20 p.i.) and the chronic phase of EAE (days 41-42 p.i.) lipids were analyzed by electrospray ionization-tandem mass spectrometry (ESI-MS), and myelin proteins by western blot in the spinal cord.
Results:
In the prevention experiment, application of infigratinib resulted in a reduction of LPC (p = 0.05) and ceramide concentrations (p = 0.01), and increased the expression of CNPase, MBP and PLP (p = 0.01) in the chronic phase. No effects on these lipids or myelin proteins were observed in the acute phase. In the suppression experiment, administration of infigratinib did not affect the concentrations of LPC or ceramide. The expression of MBP and PLP was upregulated in the acute phase (p = 0.01).
Conclusions:
Pharmacological inhibition of FGFR from the time of EAE induction resulted in a downregulation of lipids associated with neurodegeneration and enhanced myelin protein expression in the chronic phase of EAE, where neurodegeneration prevails. The underlying mechanisms of inhibition mediated lipid alterations are unclear. Inhibition of FGFR may have the potential to reduce lipid-associated neurodegeneration in EAE and MS.